Human's ability to detect chemicals though our sense of smell and taste is essential to maintain the quality of our daily life, from enjoying meals and flowers to detecting fire and spoiled food. Our long-term objective is to understand how chemicals are detected in the peripheral sense organs, how the information is processed in the brain to recognize chemicals, and how the brain directs appropriate behavioral responses. These processes are critical for animals to survive and reproduce. Without functional olfactory and gustatory systems, animals have difficulties in detecting and evaluating food, finding predators, prey, mating partners, and noxious chemicals in the environment. Although mammalian odorant receptors (ORs) were identified over 15 years ago, comprehensive understanding of how different odorant molecules interact with ORs at a molecular level has not been achieved. To address this, it is important to have a more complete understanding of the biosynthesis of ORs and OR ligand specificities. Progress on this front has been slow, largely due to the lack of an efficient system for identifying ligands that activate the ORs. In the current grant period, we have made progress in both the olfactory and gustatory systems. In the olfactory system, we identified RTP1 and RTP2, accessory molecules that enhance the cell-surface expression of ORs, enabling us to functionally express ORs in heterologous cells. Using this approach, we identified a set of active ligands for mammalian ORs. In the gustatory system, we identified PKD1L3 and PKD2L1 as candidate sour taste receptors. The Public Health Relevance: There is not a scientist or perfumer in the world who can view a novel molecular structure and predict how it will smell, largely due to a lack of knowledge about which odorant receptors are activated by a given odor. The goals of the studies proposed here are to deepen our understanding of how odorants are detected by odorant receptors. These studies may help understand olfactory dysfunction and develop new ways to improve the quality of our daily life - from enjoying meals and flowers to detecting fire and spoiled food.